1. Field of the invention
The present invention relates to a soft capsule composition containing a stable microemulsion concentrate suitable for the preparation of cyclosporin-containing soft capsules. More particularly, the present invention relates to a microemulsion concentrate containing cyclosporin as an active ingredient, dimethylisosorbide as a co-surfactant, an oil component and a surfactant, which is suitable for formulation into soft capsules and to a soft capsule composition containing said microemulsion concentrate.
2. Background art
Cyclosporin is a specific macromolecular (molecular weight 1202.64) cyclic peptide compound consisting of 11 amino acids, which has useful pharmacological activities, particularly immunosuppressive activity and anti-inflammatory activity. Therefore, cyclosporin has been used for suppression of immunological responses native to the living body, which are caused by tissue and organ transplantation, for example, transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and particularly the transplantation of foreign tissues and organs. In addition, cyclosporin is useful for the suppression of autoimmune diseases and inflammatory diseases such as arthritis, etc.
Cyclosporin is highly lipophilic and hydrophobic with a solubility in water at 25.degree. C. being 16 to 23 mg of cyclosporin per liter of water. The bioavailability of cyclosporin is also extremely low due to its low water-solubility. On the other hand, cyclosporin is well dissolved in an organic solvent such as methanol, ethanol, acetone, ether, chloroform and the like, due to its high lipophilic property.
As with other conventional drugs which are sparingly soluble in water, cyclosporin is very difficult to formulate into a preparation for oral administration due to its low water solubility and bioavailability. Further, since the bioavailability of cyclosporin may be greately influenced by the condition of each individual patient, it is very difficult to provide an effective therapeutic effect.
Moreover, it is very important to provide a uniform dosage amount and appropriate bioavailability since counterbalancing the efficacy of cyclosporin are its considerable toxic side effects such as nephrotoxicity, hepatotoxicity, among others. Accordingly, numerous studies have been extensively and widely conducted to find a preparation suitable for the effective oral administration of cyclosporin.
The prior art preparations suitable for oral administration of sparingly water-soluble cyclosporin are usually formulated in the form of a microemulsion. In preparing the liquid microemulsion formulation, cyclosporin should be combined with a surfactant, an oil and a cosurfactant. One method using this combination is taught in U.S. Pat. No. 4,388,307 which issued on Jun. 14, 1983. This patent discloses a liquid formulation of cyclosporin using ethanol as a cosurfactant. Thus, cyclosporin is combined with a carrier consisting of ethanol as a cosurfactant, a vegetable oil and a transesterification product of a natural vegetable oil triglyceride and a polyalkylene glycol as a surfactant to form the liquid formulation. However, the resulting liquid formulation is administered as an aqueous dilution making it very difficult to properly formulate the preparation to provide a uniform dosage for oral administration.
In order to alleviate the requirement of diluting the cyclosporin liquid composition in water prior to oral administration, a liquid composition in the form of a microemulsion concentrate has been formulated into a soft capsule preparation, which is presently commercially available as SANDIMMUN.RTM. (trademark). In this preparation the cyclosporin soft capsule contains a large amount of ethanol as a cosurfactant due to the solubility requirements of cyclosporin. However, since ethanol, which has a low boiling point, permeates the gelatin membrane of the capsule to volatilize even at normal temperature, the constitutional ratio of the contents in soft capsules varies during storage. The reduced ethanol content results in a significant difference in the bioavailability of cyclosporin and making the problem worse, the cyclosporin crystallizes when the soft capsules are stored at low temperature.
In an effort to prevent the volatilization of ethanol from the soft capsule preparations during storage and distribution, the soft capsule preparations are wrapped in a packing material, such as an aluminum film foam package. However, such specific packaging does not completely maintain the uniform composition of the wrapped capsule. It has been demonstrated through experiments that although the cyclosporin soft capsule is wrapped up in aluminum film foam package, the ethanol content is lowered to 7.9% from the initial level of 10.8% after a period of one week. This results in a great difference in bioavailability and may contribute to the increase of its price.
To solve the above-mentioned disadvantages which accompany the use of ethanol as a cosurfactant, a method using a non-ethanol component as a cosurfactant has been proposed. Korean Laid-open Patent Publication No. 90-4348 (Apr. 12, 1990) discloses a pharmaceutical composition in the form of a microemulsion concentrate containing a non-ethanol component. The non-ethanol components include pharmaceutically acceptable C.sub.1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of low molecular mono- or poly-oxy-alkanediol, for example, diethyleneglycol monoethyl ether [e.g. Transcutol] or tetrahydrofurfuryl alcohol polyethylene glycol ether [e.g. Glycofurol], or 1,2-propyleneglycol as a cosurfactant. However, the above non-ethanol cosurfactants are glycols which contain the -OH group in their structures. It has now been identified that the OH group-containing glycol creates problems in the formulation of soft capsules because its strong absorption property is sufficient to absorb the moisture from the atmosphere and also because it is highly permeable to the gelatin film of the soft capsule.
Thus, the present inventors have studied numerous additives, including various solvents, in an effort to find a cosurfactant capable of providing a microemulsion concentrate suitable for the formulation of cyclosporin into a soft capsule preparation. As a result, a certain pharmaceutically acceptable solvent, dimethyli- sosorbide [Trade name: ARLASOVE.RTM. DMI, available from ICI Speciality Chemicals] has been found as a suitable solvent for this purpose to complete the present invention.
Therefore, it is an object of the present invention to provide a microemulsion concentrate containing dimethylisosorbide as a cosurfactant, which is suitable for formulation into soft capsules for oral administration.
It is a further object of the present invention to provide a microemulsion concentrate suitable for formulation into soft capsules, which contains cyclosporin as an active ingredient, dimethylisosorbide as a cosurfactant, an oil component and a surfactant.
Further, it is another object of the present invention to provide a soft gelatin capsule composition according to the present invention which is highly storage stable such that there is little variation of the composition over time.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention and the drawings, in addition to the scope of the invention defined by the claims.